An enzyme-responsive and transformable PD-L1 blocking peptide-photosensitizer conjugate enables efficient photothermal immunotherapy for breast cancer.

Mild photothermal therapy combined with immune checkpoint blockade has received increasing attention for the treatment of advanced or metastatic cancers due to its good therapeutic efficacy. However, it remains a challenge to facilely integrate the two therapies and make it potential for clinical translation. This work designed a peptide-photosensitizer conjugate (PPC), which consisted of a PD-L1 antagonist peptide (CVRARTR), an MMP-2 specific cleavable sequence, a self-assembling motif, and the photosensitizer Purpurin 18. The single-component PPC can self-assemble into nanospheres which is suitable for intravenous injection. The PPC nanosphere is cleaved by MMP-2 when it accumulates in tumor sites, thereby initiating the cancer-specific release of the antagonist peptide. Simultaneously, the nanospheres gradually transform into co-assembled nanofibers, which promotes the retention of the remaining parts within the tumor. In vivo studies demonstrated that PPC nanospheres under laser irradiation promote the infiltration of cytotoxic T lymphocytes and maturation of DCs, which sensitize 4T1 tumor cells to immune checkpoint blockade therapy. Therefore, PPC nanospheres inhibit tumor growth efficiently both in situ and distally and blocked the formation of lung metastases. The present study provides a simple and efficient integrated strategy for breast cancer photoimmunotherapy.